Antimicrobial 3 protein synthesis inhibitors

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Protein Synthesis Inhibitors Prepared by Dr.Aseenat Mansour

Transcript of Antimicrobial 3 protein synthesis inhibitors

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Protein SynthesisInhibitors

Prepared byDr.Aseenat Mansour

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A number of antibiotics exert their antimicrobial effects by targeting bacterial ribosomes and inhibiting bacterial protein synthesis.

Bacterial ribosomes differ structurally from mammalian cytoplasmic ribosomes and are composed of 30S and 50S subunits (mammalian ribosomes have 40S and 60S subunits).

In general, selectivity for bacterial ribosomes minimizes potential adverse consequences encountered with the disruption of protein synthesis in mammalian host cells.

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TETRACYCLINESMechanism of action Tetracyclines enter susceptible organisms via passive

diffusion and also by an energy-dependent transport protein mechanism unique to the bacterial inner cytoplasmic membrane.

Tetracyclines concentrate intracellularly in susceptible organisms.

The drugs bind reversibly to the 30S subunit of the bacterial ribosome.

This action prevents binding of tRNA to the mRNA–ribosome complex, thereby inhibiting bacterial protein synthesis

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Antibacterial spectrum The tetracyclines are bacteriostatic antibiotics effective against

a wide variety of organisms, including gram-positive and gram-negative bacteria, protozoa, spirochetes, mycobacteria, and atypical species.

Doxycycline is commonly used in the treatment of acne and Chlamydia infections.

ResistanceThe most commonly encountered naturally occurring resistance to tetracyclines is an efflux pump that expels drug out of the cell.

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Typical therapeutic applications of tetracyclines.

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Pharmacokinetics1.Absorption: Tetracyclines are adequately absorbed after oral ingestion. Administration with dairy products or other substances

that contain divalent and trivalent cations (for example, magnesium and aluminum antacids or iron supplements) decreases absorption, particularly for tetracycline , due tothe formation of nonabsorbable chelates .

Both doxycycline and minocycline are available as oral and intravenous (IV) preparations.

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2. Distribution: The tetracyclines concentrate well in the bile, liver, kidney,

gingival fluid, and skin. They bind to tissues undergoing calcification (for example,

teeth and bones). Penetration into most body fluids is adequate. All tetracyclines cross the placental barrier and concentrate in

fetal bones and dentition.

3. Elimination: Tetracycline and doxycycline are not hepatically metabolized. Tetracycline is primarily eliminated unchanged in theUrine. Minocycline undergoes hepatic metabolism and is eliminated

to a lesser extent via the kidney.

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Adverse effects1. Gastric discomfort: Epigastric distress commonly results from

irritation of the gastric mucosa.[Note: Tetracycline should be taken on an empty stomach.]2. Effects on calcified tissues: Deposition in the bone and primary dentition occurs during the calcification process in growing children.This may cause discoloration and hypoplasia of teeth and a temporary stunting of growth.3. Hepatotoxicity Rarely hepatotoxicity may occur with high doses4. Phototoxicity: Severe sunburn may occur when patients exposed to sun or ultraviolet rays.5. Vestibular dysfunction: Dizziness, vertigo, and tinnitus may occur6. Pseudotumor cerebri: Benign, intracranial hypertension characterized by headache and blurred vision may occur rarely in adults. Contraindications: The tetracyclines should not be used in pregnant• or breast-feeding women or in children less than 8 years of age.

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GLYCYLCYCLINESTigecycline a derivative of minocycline, is the first available member of the glycylcycline antimicrobial class.

It is indicated for the treatment of complicated skin and soft tissue infections, as well as complicated intra-abdominal infections.

Tigecycline exhibits bacteriostatic action by reversibly binding to the 30S ribosomal subunit.Tigecycline exhibits broad-spectrum activity that includes methicillinresistant staphylococci (MRSA).

Tigecycline was developed to overcome the recent emergence of tetracycline class–resistant organisms

Adverse effectsSignificant nausea and vomiting. Acute pancreatitis, including fatality, has been reported with therapy.

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AMINOGLYCOSIDES

• Aminoglycosides are used for the treatment of serious infections due to aerobic gram-negative bacilli.

• However, their clinical utility is limited by serious toxicities

Mechanism of action• Aminoglycosides diffuse through porin channels in

the outer membrane of susceptible organisms.• Inside the cell, they bind the 30S ribosomal subunit.

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Antibacterial spectrum The aminoglycosides are effective for the majority of

aerobic gram negative bacilli, including those that may be multidrug resistant, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter sp.

Aminoglycosides are often combined with a β-lactam antibiotic to employ a synergistic effect.

ResistanceResistance to aminoglycosides occurs via: 1) efflux pumps 2) decreaseduptake 3) modification and inactivation by plasmid-associatedsynthesis of enzymes.

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Pharmacokinetics1. Absorption: The highly polar, polycationic structure of the aminoglycosides prevents

adequate absorption after oral administration. Therefore, all aminoglycosides (except neomycin ) must be given parenterally to achieve adequate serum levels

2. Distribution: Due to their hydrophilicity, tissue concentrations may be subtherapeutic, and penetration into most body fluids is variable. Concentrations in CSF are inadequate.

3. Elimination: More than 90% of the parenteral aminoglycosidesare excreted unchanged in the urine

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Adverse effectsTherapeutic drug monitoring of gentamicin, tobramycin, and amikacin should be done.

1. Ototoxicity: Ototoxicity (vestibular and auditory)2. Nephrotoxicity: kidney damage ranging from mild, reversible renal impairment to severe, potentially irreversible, acute tubular necrosis. 3. Neuromuscular paralysis: This adverse effect is associated with a rapid increase in concentrations

4. Allergic reactions: Contact dermatitis is a common reaction to topically applied neomycin

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MACROLIDES AND KETOLIDES

The macrolides are a group of antibiotics with a macrocyclic lactone structure to which one or more deoxy sugars are attached.Macrolides Erythromycin was the first of these drugs to find

clinical application, both as a drug of first choice and as an alternative to penicillin in individuals with an allergy to β-lactam antibiotics.

Clarithromycin (a methylated form of erythromycin). Azithromycin(having a larger lactone ring)

Erythromycin

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Ketolides• Telithromycin:a semisynthetic derivative of

erythromycin.• Ketolides and macrolides have similar

antimicrobial coverage. • ketolides are active against many macrolide-

resistant gram-positive strains.

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Mechanism of action

• The macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thus inhibiting translocation steps of protein synthesis.

• They may also interfere with other steps, such as transpeptidation.

• Generally considered to be bacteriostatic, they may be bactericidal at higher doses.

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Antibacterial spectrum

1. Erythromycin: This drug is effective against many of the same organisms as penicillin G . Therefore, it may be used in patients with penicillin allergy.

2. Clarithromycin: Clarithromycin has activity similar to erythromycin, but it is also effective against Haemophilus influenzae.

Its activity against intracellular pathogens, such as Chlamydia, Legionella, Moraxella, Ureaplasma species and Helicobacter pylori, is higher than that of erythromycin.

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3. Azithromycin: less active against streptococci and staphylococci than

erythromycin, azithromycin.

More active against respiratory infections due to H. influenzae and Moraxella catarrhalis.

Extensive use of azithromycin has resulted in growing Streptococcus pneumoniae resistance.

Azithromycin is the preferred therapy for urethritis caused by Chlamydia trachomatis.

Mycobacterium avium is preferentially treated with a macrolide-containing regimen, including clarithromycin or azithromycin.

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4. Telithromycin: This drug has an antimicrobial spectrum

similar to that of azithromycin. The structural modification within ketolides

neutralizes the most common resistance mechanisms that make macrolides

ineffective.

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ResistanceResistance to macrolides is associated with: 1) the inability of the organism to take up the

antibiotic,2) the presence of efflux pumps, 3) A decreased affinity of the 50S ribosomal

subunit for the antibiotic

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Pharmacokinetics

1. Administration: The erythromycin base is destroyed by gastric acid. Thus, either

enteric-coated tablets or esterified forms of the antibiotic are administered.

All are adequately absorbed upon oral administration. Clarithromycin, azithromycin, and telithromycin are stable in

stomach acid and are readily absorbed.

Food interferes with the absorption of erythromycin and azithromycin but can increase that of clarithromycin.

Erythromycin and azithromycin are available in IV formulations.

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2. Distribution: Erythromycin distributes well to all body fluids except the CSF. All four drugs concentrate in the liver. Clarithromycin, azithromycin, and telithromycin are widely

distributed in the tissues.

3. Elimination: Erythromycin and telithromycin are extensively metabolized

hepatically. They inhibit the oxidation of a number of drugs through their

interaction with the cytochrome P450 system. clarithromycin Interferes with the metabolism of drugs, such as

theophylline, statins, and numerous antiepileptics, has been reported.

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4. Excretion: • Erythromycin and azithromycin are primarily

concentrated and excreted in the bile as active Partial reabsorption occurs through the enterohepatic circulation.

• In contrast, clarithromycin and its metabolites are eliminated by the kidney as well as the liver.

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Adverse effects1. Gastric distress and motility (especially with erythromycin)2. Cholestatic jaundice3. Ototoxicity: Transient deafness has been associated with erythromycin, especially at high dosages.

Contraindications: Patients with hepatic dysfunction should be treated cautiously with erythromycin, telithromycin, or azithromycin,because these drugs accumulate in the liver.

Drug interactions: Erythromycin, telithromycin, and clarithromycin inhibit the hepatic metabolism of a number of drugs, which can lead to toxic accumulation of these compounds.

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CHLORAMPHENICOLThe use of chloramphenicol , a broad-spectrum antibiotic, is restricted to life-threatening infections for which no alternatives exist.

Mechanism of actionChloramphenicol binds reversibly to the bacterial 50S ribosomal subunit and inhibits protein synthesis at the peptidyl transferase reaction.

Antibacterial spectrum• Chloramphenicol is active against many types of microorganisms

including chlamydiae, rickettsiae, spirochetes, and anaerobes. • The drug is primarily bacteriostatic, but depending on the dose

and organism, it may be bactericidal.

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Pharmacokinetics Chloramphenicol is administered intravenously and is

widely distributed throughout the body. It reaches therapeutic concentrations in the CSF. Chloramphenicol primarily undergoes hepatic metabolism

to an inactive glucuronide, which is secreted by the renal tubule and eliminated in the urine.

Dose reductions are necessary in patients with liver dysfunction or cirrhosis.

It is also secreted into breast milk and should be avoided in breastfeeding mothers.

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Adverse effects

1. Anemias: Patients may experience dose-related anemia, hemolytic anemia (seen in patients with glucose-6-phosphate dehydrogenase deficiency), and aplastic anemia.

2. Gray baby syndrome: Neonates have a decreased ability to excrete the drug, which accumulates to levels that interfere with the function of mitochondrial ribosomes.

This leads to poor feeding, depressed breathing, cardiovascular collapse, cyanosis (hence the term “gray baby”), and death.

Adults who have received very high doses of the drug can also exhibit this toxicity.

Drug interactions: Chloramphenicol inhibits some of the hepatic mixed-function oxidases and, thus, blocks the metabolism of drugs such as warfarin and phenytoin

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CLINDAMYCIN Clindamycin has a mechanism of action that is the same as

that of erythromycin. Clindamycin is used primarily in the treatment of infections

caused by gram-positive organisms, including MRSA and streptococcus, and anaerobic bacteria.

It distributes well into all body fluids including bone, but exhibits poor entry into the CSF.

Clindamycin is available in both IV and oral formulations, but use of the oral form is limited by gastrointestinal intolerance.

Clindamycin undergoes extensive oxidative metabolism to inactive products and is primarily excreted into the bile

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QUINUPRISTIN/DALFOPRISTIN

• QUINUPRISTIN/DALFOPRISTIN is a mixture of two streptogramins in a ratio of 30 to 70, respectively.

• Due to significant adverse effects, the drug is normally reserved for the treatment of severe vancomycin-resistant Enterococcus faecium (VRE) in the absence of other therapeutic options.

Mechanism of action• Each component of this combination drug binds

to a separate site on the 50S bacterial ribosome.

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LINEZOLIDLINEZOLID is a synthetic oxazolidinone developed to combat resistant gram-positive organisms, such as methicillin-resistant Staphylococcus aureus, VRE, and penicillin-resistant streptococci.

Mechanism of actionLinezolid binds to the bacterial 23S ribosomal RNA of the 50S subunit, thereby inhibiting the formation of the 70S initiation complex. Linezolid is completely absorbed after oral administration. An IV preparation is also available. The drug is widely distributed throughout the body.

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